TY - JOUR T1 - Epigenetic suppression of SLFN11 in germinal center B cells in the process of the dynamic expression change during B-cell development JF - bioRxiv DO - 10.1101/2020.07.30.228650 SP - 2020.07.30.228650 AU - Fumiya Moribe AU - Momoko Nishikori AU - Hiroyuki Sasanuma AU - Remi Akagawa AU - Hiroshi Arima AU - Shunichi Takeda AU - Akifumi Takaori-Kondo AU - Junko Murai Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/07/30/2020.07.30.228650.abstract N2 - Background SLFN11 enhances cellular toxicity of genotoxic anti-cancer agents, and its important role under physiological conditions has not been appreciated yet. Somatic hypermutations and class switch recombination that can cause physiological genotoxic stress arise in germinal center B cells (GCBs). GCBs are a major origin of B-cell lymphomas that are frequently treated by cytosine arabinoside, a genotoxic anti-cancer agent.Objective To clarify the expression profile of SLFN11 in different stages of B cells and B-cell lymphomas.Methods We analyzed the expression of SLFN11 by mining publicly available databases for different stages of normal B cells and various types of B-cell lymphoma lines and also by performing immunohistochemical staining of human lymph nodes. We investigated the effects of two epigenetic modifiers, an EZH2 inhibitor, tazemetostat (EPZ6438) and a histone deacetylase inhibitor, panobinostat (LBH589) on SLFN11 expression in B-cell lymphoma lines and examined the therapeutic efficacy of these epigenetic modifiers in the combination with cytosine arabinoside.Results SLFN11 expression was specifically low in GCBs compared to non-GCBs, which was consolidated by the immunohistochemical staining for SLFN11 with human lymph nodes. SLFN11 expression levels in B-cell lymphoma lines largely correlated to those of their normal counterparts. The epigenetic modifiers upregulated SLFN11 expression in GCB-derived lymphomas and made the lymphomas further susceptible to cytosine arabinoside.Conclusions The expression of SLFN11 may be epigenetically suppressed in GCBs and GCB-derived lymphomas. GCB-derived lymphomas with low SLFN11 expression can be treated by the combination of epigenetic modifiers and cytosine arabinoside. ER -